Diagnosis of Whipple Disease
Diagnosis
Almost all patients with Whipples disease have involvement of the intestinal tract by this infection, regardless of whether gastrointestinal symptoms are present. Thus, the primary diagnostic approach to a patient with clinical suspicion of possible Whipples disease is upper endoscopy with mucosal biopsy. To avoid sampling errors in patients with patchy lesions of Whipples disease, one should obtain approximately five biopsy specimens from regions as far distal as possible within the small intestines.Histologic examination with use of routine and PAS stains is usually sufficient to reach a diagnosis. In some cases, the findings may be corroborated with silver stains ; in contrast, the Gram stain is less useful in this infection.
Immunocytochemistry with cross-reactive antisera directed against other bacteria may show positive reactions that colocalize with PAS-positive inclusions, but this has not found practical use in histopathology. It remains to be seen whether specific antisera raised against T. whippelii will prove useful in histopathologic practice. Traditionally, electron microscopy has been used as the gold standard for confirming the diagnosis of Whipples disease. Currently, PCR analysis serves in this capacity.
After the molecular characterization of T. whippelii, several PCR-based assays have been developed for diagnostic purposes.However, many of these assays have not been thoroughly validated with measurement of performance characteristics and adequate identification of amplified products. In almost all patients with a histologic diagnosis of Whipples disease, well-standardized PCR assays detect T. whippelii DNA in the intestinal mucosa.In contrast, intestinal biopsies with normal histology are almost always negative for DNA of T. whippelii. In practical terms, a normal intestinal histology in the absence of extraintestinal disease suggestive of Whipples disease bona fide rules out the diagnosis, provided that multiple biopsy specimens are evaluated.
Extraintestinal manifestations warrant the examination of specimens from affected sites. Histology and cytology with PAS staining, electron microscopy, and PCR are all useful for this purpose. Since the introduction of PCR for T. whippelii, some patients have been reported with a PCR-based diagnosis of T. whippelii infection in extraintestinal samples, whereas intestinal histology (when tested) was negative for PAS-positive macrophages. Examples of such patients are a case of febrile illness with erythrocyte-associated bacteria,a case of uveitis,and cases of valvular heart disease.The small number of reported cases suggests that these are rare events, although there have been few prospective studies of extraintestinal syndromes suggestive of Whipples disease. PCR testing of peripheral blood samples has been proposed as a potential noninvasive screening method,but its diagnostic usefulness has been questioned.
Considering the systemic nature of this disorder, it is important to evaluate commonly involved organ systems when a new diagnosis of Whipples disease has been reached. Ultrasound examination may reveal enlarged mesenteric lymph nodes that have unusually high echogenicity due to lipid deposits.Neurologic examination is indicated, including routine sampling of CSF. Based on cytologic or PCR analysis, 70% of patients with intestinal Whipples disease in one study were found to have CNS infection with T. whippelii, even though they had no neurologic or psychiatric symptoms. Imaging studies of the brain are generally not helpful in patients without neurologic symptoms.
During treatment, one should repeat diagnostic assessments at regular intervals. Endoscopic lesions usually resolve within some months but may last for up to a year. Intestinal histology improves within several months,and PCR assays on intestinal biopsy tissues convert to negative within a wide time range (1 to 12 months) after institution of appropriate therapy.Some PAS-positive macrophages may persist for years,even while the patient remains in clinical remission (see earlier). Regression of enlarged abdominal lymph nodes may require more than a year and may result in fibrosis. Follow-up examination of the CSF is most effectively performed with inclusion of PCR analysis.
Almost all patients with Whipples disease have involvement of the intestinal tract by this infection, regardless of whether gastrointestinal symptoms are present. Thus, the primary diagnostic approach to a patient with clinical suspicion of possible Whipples disease is upper endoscopy with mucosal biopsy. To avoid sampling errors in patients with patchy lesions of Whipples disease, one should obtain approximately five biopsy specimens from regions as far distal as possible within the small intestines.Histologic examination with use of routine and PAS stains is usually sufficient to reach a diagnosis. In some cases, the findings may be corroborated with silver stains ; in contrast, the Gram stain is less useful in this infection.
Immunocytochemistry with cross-reactive antisera directed against other bacteria may show positive reactions that colocalize with PAS-positive inclusions, but this has not found practical use in histopathology. It remains to be seen whether specific antisera raised against T. whippelii will prove useful in histopathologic practice. Traditionally, electron microscopy has been used as the gold standard for confirming the diagnosis of Whipples disease. Currently, PCR analysis serves in this capacity.
After the molecular characterization of T. whippelii, several PCR-based assays have been developed for diagnostic purposes.However, many of these assays have not been thoroughly validated with measurement of performance characteristics and adequate identification of amplified products. In almost all patients with a histologic diagnosis of Whipples disease, well-standardized PCR assays detect T. whippelii DNA in the intestinal mucosa.In contrast, intestinal biopsies with normal histology are almost always negative for DNA of T. whippelii. In practical terms, a normal intestinal histology in the absence of extraintestinal disease suggestive of Whipples disease bona fide rules out the diagnosis, provided that multiple biopsy specimens are evaluated.
Extraintestinal manifestations warrant the examination of specimens from affected sites. Histology and cytology with PAS staining, electron microscopy, and PCR are all useful for this purpose. Since the introduction of PCR for T. whippelii, some patients have been reported with a PCR-based diagnosis of T. whippelii infection in extraintestinal samples, whereas intestinal histology (when tested) was negative for PAS-positive macrophages. Examples of such patients are a case of febrile illness with erythrocyte-associated bacteria,a case of uveitis,and cases of valvular heart disease.The small number of reported cases suggests that these are rare events, although there have been few prospective studies of extraintestinal syndromes suggestive of Whipples disease. PCR testing of peripheral blood samples has been proposed as a potential noninvasive screening method,but its diagnostic usefulness has been questioned.
Considering the systemic nature of this disorder, it is important to evaluate commonly involved organ systems when a new diagnosis of Whipples disease has been reached. Ultrasound examination may reveal enlarged mesenteric lymph nodes that have unusually high echogenicity due to lipid deposits.Neurologic examination is indicated, including routine sampling of CSF. Based on cytologic or PCR analysis, 70% of patients with intestinal Whipples disease in one study were found to have CNS infection with T. whippelii, even though they had no neurologic or psychiatric symptoms. Imaging studies of the brain are generally not helpful in patients without neurologic symptoms.
During treatment, one should repeat diagnostic assessments at regular intervals. Endoscopic lesions usually resolve within some months but may last for up to a year. Intestinal histology improves within several months,and PCR assays on intestinal biopsy tissues convert to negative within a wide time range (1 to 12 months) after institution of appropriate therapy.Some PAS-positive macrophages may persist for years,even while the patient remains in clinical remission (see earlier). Regression of enlarged abdominal lymph nodes may require more than a year and may result in fibrosis. Follow-up examination of the CSF is most effectively performed with inclusion of PCR analysis.
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